The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability
Interleukin-2 is central to the induction and maintenance of both natural (nT<sub>reg</sub>) and induced Foxp3-expressing regulatory T cells (iT<sub>reg</sub>). Thus, signals that modulate IL-2 availability may, in turn, also influence T<sub>reg</sub> homeostasis....
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/17/2639 |
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| author | Bernd Geers Julia Hagenstein Jessica Endig Hanna Ulrich Laura Fleig Paulina Sprezyna Julita Mikulec Lukas Heukamp Gisa Tiegs Linda Diehl |
| author_facet | Bernd Geers Julia Hagenstein Jessica Endig Hanna Ulrich Laura Fleig Paulina Sprezyna Julita Mikulec Lukas Heukamp Gisa Tiegs Linda Diehl |
| author_sort | Bernd Geers |
| collection | DOAJ |
| description | Interleukin-2 is central to the induction and maintenance of both natural (nT<sub>reg</sub>) and induced Foxp3-expressing regulatory T cells (iT<sub>reg</sub>). Thus, signals that modulate IL-2 availability may, in turn, also influence T<sub>reg</sub> homeostasis. Using global knockout and cell-specific knockout mouse models, we evaluated the role of the small GTPase ADP-ribosylation factor 4d (Arl4d) in regulatory T-cell biology. We show that the expression of Arl4d in T cells restricts both IL-2 production and responsiveness to IL-2, as measured by the phosphorylation of STAT5. <i>Arl4d</i>-deficient CD4 T cells converted more efficiently into Foxp3<sup>+</sup> iT<sub>reg</sub> in vitro in the presence of αCD3ε and TGFβ, which was associated with their enhanced IL-2 secretion. As such, <i>Arl4d</i><sup>−/−</sup> CD4 T cells induced significantly less colonic inflammation and lymphocytic infiltration in a model of transfer colitis. Thus, our data reveal a negative regulatory role for Arl4d in CD4 T-cell biology, limiting iT<sub>reg</sub> conversion via the restriction of IL-2 production, leading to reduced induction of T<sub>reg</sub> from conventional CD4 T cells. |
| first_indexed | 2024-03-10T01:56:45Z |
| format | Article |
| id | doaj.art-4c2dc861e00d45b7b722d498acbf38b2 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:56:45Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4c2dc861e00d45b7b722d498acbf38b22023-11-23T12:54:24ZengMDPI AGCells2073-44092022-08-011117263910.3390/cells11172639The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 AvailabilityBernd Geers0Julia Hagenstein1Jessica Endig2Hanna Ulrich3Laura Fleig4Paulina Sprezyna5Julita Mikulec6Lukas Heukamp7Gisa Tiegs8Linda Diehl9Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Experimental Medicine, University Hospital Bonn, 53127 Bonn, GermanyInstitute for Hematopathology, 22547 Hamburg, GermanyInstitute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInterleukin-2 is central to the induction and maintenance of both natural (nT<sub>reg</sub>) and induced Foxp3-expressing regulatory T cells (iT<sub>reg</sub>). Thus, signals that modulate IL-2 availability may, in turn, also influence T<sub>reg</sub> homeostasis. Using global knockout and cell-specific knockout mouse models, we evaluated the role of the small GTPase ADP-ribosylation factor 4d (Arl4d) in regulatory T-cell biology. We show that the expression of Arl4d in T cells restricts both IL-2 production and responsiveness to IL-2, as measured by the phosphorylation of STAT5. <i>Arl4d</i>-deficient CD4 T cells converted more efficiently into Foxp3<sup>+</sup> iT<sub>reg</sub> in vitro in the presence of αCD3ε and TGFβ, which was associated with their enhanced IL-2 secretion. As such, <i>Arl4d</i><sup>−/−</sup> CD4 T cells induced significantly less colonic inflammation and lymphocytic infiltration in a model of transfer colitis. Thus, our data reveal a negative regulatory role for Arl4d in CD4 T-cell biology, limiting iT<sub>reg</sub> conversion via the restriction of IL-2 production, leading to reduced induction of T<sub>reg</sub> from conventional CD4 T cells.https://www.mdpi.com/2073-4409/11/17/2639regulatory T cellFoxp3pSTAT5interleukin 2Arl4dimmune regulation |
| spellingShingle | Bernd Geers Julia Hagenstein Jessica Endig Hanna Ulrich Laura Fleig Paulina Sprezyna Julita Mikulec Lukas Heukamp Gisa Tiegs Linda Diehl The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability Cells regulatory T cell Foxp3 pSTAT5 interleukin 2 Arl4d immune regulation |
| title | The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability |
| title_full | The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability |
| title_fullStr | The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability |
| title_full_unstemmed | The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability |
| title_short | The ADP-Ribosylation Factor 4d Restricts Regulatory T-Cell Induction via Control of IL-2 Availability |
| title_sort | adp ribosylation factor 4d restricts regulatory t cell induction via control of il 2 availability |
| topic | regulatory T cell Foxp3 pSTAT5 interleukin 2 Arl4d immune regulation |
| url | https://www.mdpi.com/2073-4409/11/17/2639 |
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